論文 - 詳細
| RRC ID | 18145 |
|---|---|
| 著者 | Abiko Y, Miura T, Phuc BH, Shinkai Y, Kumagai Y. |
| タイトル | Participation of covalent modification of Keap1 in the activation of Nrf2 by tert-butylbenzoquinone, an electrophilic metabolite of butylated hydroxyanisole. |
| ジャーナル | Toxicol Appl Pharmacol |
| Abstract |
Butylated hydroxyanisole (BHA) is an antioxidant and class-2B carcinogen. It is biotransformed to tert-butylhydroquinone (TBHQ), which readily auto-oxidizes to the electrophilic metabolite tert-butylbenzoquinone (TBQ). BHA and TBHQ activate Nrf2, a transcription factor that is negatively regulated by Keap1 and plays a role in the initial response to chemicals causing oxidative or electrophilic stress, although, the exact mechanism of Nrf2 activation remains unclear. Here, we examined the role of TBQ in Nrf2 activation. Exposure of RAW264.7 cells to TBQ activated Nrf2 and up-regulated its downstream proteins; under these conditions, TBQ produced cellular reactive oxygen species (ROS). However, while pretreatment with catalase conjugated with polyethylene glycol (PEG-CAT) did not affect the TBQ-induced activation of Nrf2, the ROS generation caused by TBQ was entirely abolished by PEG-CAT, suggesting that ROS is not the dominant factor for TBQ-dependent Nrf2 activation. A click chemistry technique indicated that TBQ chemically modifies Keap1. Furthermore, ultrahigh performance liquid chromatography-tandem mass spectrometry analysis with purified Keap1 revealed that TBQ covalently binds to Keap1 through Cys23, Cys151, Cys226, and Cys368. These results suggest that TBQ derived from BHA activates Nrf2 through electrophilic modification of Keap1 rather than ROS formation. |
| 巻・号 | 255(1) |
| ページ | 32-9 |
| 公開日 | 2011-8-15 |
| DOI | 10.1016/j.taap.2011.05.013 |
| PII | S0041-008X(11)00192-X |
| PMID | 21651925 |
| MeSH | Adaptor Proteins, Signal Transducing / metabolism* Amino Acid Sequence Animals Benzoquinones / pharmacology* Butylated Hydroxyanisole / metabolism* Cell Survival / drug effects Cells, Cultured Cysteine / chemistry Cytoskeletal Proteins / metabolism* Hydroquinones / metabolism Kelch-Like ECH-Associated Protein 1 Mice Molecular Sequence Data NF-E2-Related Factor 2 / metabolism* Reactive Oxygen Species / metabolism |
| IF | 3.347 |
| 引用数 | 55 |
| WOS 分野 | PHARMACOLOGY & PHARMACY TOXICOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | RAW 264(RCB0535) |